Running Reactions: The Journey and the Destination

I was running a Curtius rearrangement last week and it struck me that this was exactly the kind of reaction I like to run, one with several steps, the kind of reaction that you have to base your entire day around.

For those who don’t know it, the Curtius involves forming an acyl azide, which rearranges to an isocyanate (releasing nitrogen in the process), which can then be either hydrolyzed to an amine or condensed with an alcohol (to form a carbamate) or an amine (to form a urea). It is a very neat way of changing an acid into an amine. But more to the point of my post, there are several stages in the procedure: formation of the acyl azide, which is usually accomplished by careful addition of diphenyl phosphoryl azide to a solution of your acid, then inducing the rearrangement by heating, then I cooled it back down to add an amine (I was making a urea), before heating it up again to push the condensation reaction to completion.

Thinking more about it, this kind of reaction is a luxury. Most of the lab work goes into purifying and analyzing compounds, not the reaction itself. So to take time to run the reaction, to enjoy the journey as it were, is something that the average busy laboratory chemist doesn’t get the chance to do a lot. Or when they do, it is artistically arranged around group meetings, seminars and any other work you’ve got going on. In short, enjoying the journey can make life a lot more stressful.

Which is of course why the medicinal chemist’s stock-in-trade reactions are amide couplings, Suzuki reactions and reductive aminations. Reactions for which the procedure reads “put everything in the flask and mix it up”. For these reactions, the destination is the thing and the hustle and bustle of the journey is avoided as much as possible. You set it up, get on with other stuff, then come back and it is done. The perfect reaction to set up late in the afternoon, then you come back next morning to complete reactions, spot-to-spot conversions with hardly any need for purification. Or, more usually, it flows into a morning of work-ups and purification, which is the usual way we spend our day.

Maybe it is a change on time – or the stage of my own career. When making a ketone or aldehyde, the way I always did it in graduate school was via a Swern oxidation. It had the advantage of high yields, clean reaction and also a satisfyingly involved reaction procedure. Plus it was a mechanism that came up practically every week in group meetings. There was that little problem with the smell of the dimethyl sulfide by-product. But nothing is perfect.

I can’t actually recall the last time I did an oxidation that way. Dess-Martin periodinane, sure. Even a manganese dioxide oxidation. But the Swern seems to be too much of a luxury when easier and more straightforward methods are available.

But sometimes it is worthwhile to slow down and enjoy the process of running a reaction, enjoying the color changes that tell you everything is working and the satisfaction at the end of a product you worked, really worked, to obtain.


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